Identification and biological evaluation of novel indole-2-one derivatives as BRD4-BD2 inhibitors

Pan-inhibitions of Bromodomain and Extra Terminal Domain (BET) proteins have shown great potential in anti-tumor therapy but exhibited clinical toxicities, while selective inhibition of BRD4-BD2 could improve specificity and have better safety. Herein, a series of indole-2-one derivatives were designed and synthesized as novel BD2-selective inhibitors. The representative compound 47 showed good inhibitory effect on BRD4-BD2 with the IC₅₀ of 27 nM and displayed 102-fold selectivity over BRD4-BD1, and exhibited extensive anti-tumor proliferation activities in vitro, especially against tumor cells, such as K562 and HGC-27 (IC₅₀ = 0.15 and 3 μM), and it was less toxic to normal cell in GES-1 (IC₅₀ = 71 μM). Further biological studies revealed that 47 could down-regulate c-Myc and up-regulate p21, arrest cell cycle at G₀/G₁ phase and induce apoptosis in HGC-27 cells. More importantly, 47 showed moderate pharmacokinetic properties and low toxicity in vivo. These results demonstrated that 47 might serve as a potent lead compound with potential for the treatment of cancers such as gastric cancer.